The GD3 ganglioside is a glycosphingolipid that is over expressed on melanoma cells. Thus, the GD3 ganglioside is an attractive target for immunotherapy of melanoma. At present, there is no effective therapeutic regimen approved for advanced melanoma which results in a sustained benefit. The treatment guidelines that exist in most countries focus primarily on surgery to remove malignant melanoma and there is little if any guidance on the selection of chemotherapy or immunotherapy regimens. Even between experts, there is little if any agreement on treatment options.
In Stages I-III of the disease, surgery is generally the first line treatment, followed by adjuvant (post-resection) treatment using recombinant IFN alpha2 products (Schering Plough's Intron A™), or various combinations of chemotherapeutic regimens, although there is no demonstrated sustained survival benefit in the rIFN treatment regimens. For Stage IV patients, where the disease has metastasised, treatments used tend to be chemotherapy or high-dose IFN alpha2, but the prognosis for such patients is very poor, with a very low (9%) response rate and a median survival rate of six to nine months. A significant proportion of Stage II+III patients also are at risk of developing metastatic disease. Due to the bleak outlook for Stage IV patients, most are enrolled in clinical trials for developing therapeutics.
Previous work has identified a mouse IgG3 monoclonal antibody, known as R24, that binds to the GD3 ganglioside. This antibody has been shown to exhibit a phenomenon known as homophilic binding, whereby the antibodies bind to each other. Furthermore, although IgG3 mouse antibodies are not particularly efficient at fixing human complement, it has been found that R24 was active in vitro with respect to complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) (Chapman et al., J. Immunol. (1990) 145(3): 891-898).
The murine R24 antibody has been used in the treatment of malignant melanoma. A considerable number of clinical trials have been conducted with the murine R24 antibody in patients with late stage malignant melanoma, either alone or in combination with other agents, and these have had some success with regards to tumour regression. However, the antibody elicited some immunogenic responses in a significant proportion of patients owing to the fact that it was murine in nature (Bajorin, D. F. et al., Melanoma Research (1992) 2 (5-6): 355-362). For this reason, dosing was restricted and the treatment regimens were not able to be optimised.
A chimeric mouse-human version of the R24 antibody has been generated. However, this chimeric antibody exhibited a substantially lower level of binding to the GD3-binding site compared to the murine R24 antibody. In addition, while the chimeric antibody maintained the characteristics of homophilic binding and fixing human complement, the efficiency of ADCC was slightly reduced. This chimeric antibody is formed from entire murine antibody heavy chain and light chain variable regions engineered onto human heavy chain and light chain constant regions as described in Chapman et al., Cancer Immunol. Immunother. (1994) 39: 198-204.
There are other known monoclonal mouse antibodies that bind to the GD3 ganglioside, such as the KM-641 antibody produced by a hybridoma KM.-641. Chimeric versions of these antibodies, e.g., KM-871, are also known (see U.S. Pat. No. 6,437,098). These chimeric versions are also formed from entire murine antibody heavy chain and light chain variable regions engineered onto human heavy chain and light chain constant regions.
Most therapies in development are targeting the earlier, non-metastatic stages of malignant melanoma, owing to the difficulties in obtaining a response when the disease has metastasised. There are very few immunotherapeutics targeting Stage IV melanoma.
Thus, there is clearly a significant demand for an effective treatment, particularly for advanced malignant melanoma, but also melanoma generally.